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Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms. Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration. However, recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration, particularly in the context of traumatic injuries. Consequently, autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration. Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths, thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation. These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration. A range of autophagy-inducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries. This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration, summarizing the potential drugs and interventions that can be harnessed to promote this process. We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.

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Cryo-electron microscopy is a powerful methodology in structural biology and has been broadly used in high-resolution structure determination for challenging samples, which are not readily available for traditional techniques. In particular, the strength of super macro-complexes and the lack of a need for crystals for cryo-EM make this technique feasible for the structural study of complexes involved in antiviral innate immunity. This chapter presents detailed information and experimental procedures of Cryo-EM for determining the structures of the complexes using STING as an example. The procedures included a sample quality check, high-resolution data acquisition, and image processing for Cryo-EM 3D structure determination.

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ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of Qi and blood in Traditional Chinese Medicine (TCM), the combination of Qi-reinforcing herbs and blood-activating herbs has a synergistic effect in improving blood stasis syndrome, especially in tumor treatment. The classic "Radix Astragali - Salvia miltiorrhiza" duo exemplifies this principle, renowned for invigorating Qi and activating blood flow, employed widely in tumor therapies. Our prior research underscores the potent inhibition of pancreatic tumor xenografts by the combination of Formononetin (from Radix Astragali) and Salvianolic acid B (from Salvia miltiorrhiza) in vitro. However, it remains unclear whether this combination can inhibit the abnormal vascularization of pancreatic tumors to achieve its anti-cancer effect. AIM OF THE STUDY: Abnormal vasculature, known to facilitate tumor growth and metastasis. Strategies to normalize tumor-associated blood vessels provide a promising avenue for anti-tumor therapy. This study aimed to unravel the therapeutic potential of Formononetin combined with Salvianolic acid B (FcS) in modulating pancreatic cancer's impact on endothelial cells, illuminate the underlying mechanisms that govern this therapeutic interaction, thereby advancing strategies to normalize tumor vasculature and combat cancer progression. MATERIALS AND METHODS: A co-culture system involving Human Umbilical Vein Endothelial Cells (HUVECs) and PANC-1 cells was established to investigate the potential of targeting abnormal vasculature as a novel anti-tumor therapeutic strategy. We systematically compared HUVEC proliferation, migration, invasion, and lumenogenesis in both mono- and co-culture conditions with PANC-1 (H-P). Subsequently, FcS treatment of the H-P system was evaluated for its anti-angiogenic properties. Molecular docking was utilized to predict the interactions between Formononetin and Salvianolic acid B with RhoA, and the post-treatment expression of RhoA in HUVECs was assessed. Furthermore, we utilized shRhoA lentivirus to elucidate the role of RhoA in FcS-mediated effects on HUVECs. In vivo, a zebrafish xenograft tumor model was employed to assess FcS's anti-tumor potential, focusing on cancer cell proliferation, migration, apoptosis, and vascular development. RESULTS: FcS treatment demonstrated a significant, dose-dependent inhibition of PANC-1-induced alterations in HUVECs, including proliferation, migration, invasion, and tube formation capabilities. Molecular docking analyses indicated potential interactions between FcS and RhoA. Further, FcS treatment was found to downregulate RhoA expression and modulated the PI3K/AKT signaling pathway in PANC-1-induced HUVECs. Notably, the phenotypic inhibitory effects of FcS on HUVECs were attenuated by RhoA knockdown. In vivo zebrafish studies validated FcS's anti-tumor activity, inhibiting cancer cell proliferation, metastasis, and vascular sprouting, while promoting tumor cell apoptosis. CONCLUSIONS: This study underscores the promising potential of FcS in countering pancreatic cancer-induced endothelial alterations. FcS exhibits pronounced anti-abnormal vasculature effects, potentially achieved through downregulation of RhoA and inhibition of the PI3K/Akt signaling pathway, thereby presenting a novel therapeutic avenue for pancreatic cancer management.

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BACKGROUND: Although progress has been made in accurate diagnosis and targeted treatments, breast cancer (BC) patients with metastasis still present a grim prognosis. With the continuous emergence and development of new personalized and precision medicine targeting specific tumor biomarkers, there is an urgent need to find new metastatic and prognostic biomarkers for BC patients. METHODS: We were dedicated to identifying genes linked to metastasis and prognosis in breast cancer through a combination of in silico analysis and experimental validation. RESULTS: A total of 25 overlap differentially expressed genes were identified. Ten hub genes (namely MRPL13, CTR9, TCEB1, RPLP0, TIMM8B, METTL1, GOLT1B, PLK2, PARL and MANBA) were identified and confirmed. MRPL13, TCEB1 and GOLT1B were shown to be associated with the worse overall survival (OS) and were optionally chosen for further verification by western blot. Only MRPL13 was found associated with cell invasion, and the expression of MRPL13 in metastatic BC was significantly higher than in primary BC. CONCLUSION: We proposed MRPL13 could be a potential novel biomarker for the metastasis and prognosis of breast cancer.

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Polychlorinated naphthalenes (PCNs) are detrimental to human health and the environment. With the commercial production of PCNs banned, unintentional releases have emerged as a significant environmental source. However, relevant information is still scarce. In this study, provincial emissions for eight PCNs homologues from 37 sources in the Chinese mainland during the period of 1960-2019 were estimated based on a source-specific and time-varying emission factor database. The results showed that the total PCNs emissions in 2019 reached 757.0 kg with Hebei ranked at the top among all the provinces and iron & steel industry as the biggest source. Low-chlorinated PCNs comprised 90% of emissions by mass, while highly chlorinated PCNs dominated in terms of toxicity, highlighting divergent priorities for mitigating emissions and safeguarding human health. The emissions showed an overall upward trend from 1960 to 2019 driven by emission increase from iron & steel industry in terms of source, and from North China and East China in terms of geographic area. Per-capita emissions followed an inverted U-shaped environmental Kuznets curve while emission intensities decreased with increasing per-capita Gross Domestic Product (GDP) following a nearly linear pattern when log-transformed.

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Reducing pesticide residues while extending their efficacy period is a critical challenge in the development of controlled-release pesticides. This study focuses on loading avermectin onto lignin-modified epoxy resin nanocarriers via the creation of photostable nanocapsules (NCs) for evaluating their efficacy against Plutella xylostella. This study also assesses the NCs' resistance to water scour on plant leaves by comparing them with traditional preparations. These NCs feature a stable core-shell structure, an encapsulation efficiency of 92.90 % and slow-release properties. Compared to emulsifiable concentrate (EC) and microemulsion (ME) under UV irradiation, the loading of nanocarriers significantly prolonged the degradation time of avermectin by fivefold. The Nano-formula demonstrated enhanced insecticidal activity in comparison to traditional preparations. Field tests revealed that the efficacy of the NCs on Day 7 (92.55 %) and Day 14 (78.54 %) significantly surpassed that of traditional preparations. Additionally, NCs are more readily washed off cabbage leaves by water than EC and ME, aiding in the reduction of pesticide residues. This technology is particularly suitable for leafy vegetable crops in arid regions or greenhouses, enhancing effectiveness period while minimizing pesticide residues. This research offers novel insights and directions for the development of controlled-release pesticides.

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Cadmium (Cd) is one of the most toxic elements to all organisms. Glutathione (GSH)-dependent phytochelatin (PC) synthesis pathway is considered an extremely important mechanism in Cd detoxification in plants. However, few studies have focused on the roles of glutamate-cysteine ligase (GSH1) and phytochelatin synthase (PCS1) in Cd accumulation and detoxification in plants. In this study, SpGSH1 and SpPCS1 were identified and cloned from Spirodela polyrhiza and analyzed their functions in yeast and S. polyrhiza via single- or dual-gene (SpGP1) overexpression. The findings of this study showed that SpGSH1, SpPCS1, and SpGP1 could dramatically rescue the growth of the yeast mutant Δycf1. In S. polyrhiza, SpGSH1 was located in the cytoplasm and could promote Mn and Ca accumulation. SpPCS1 was located in the cytoplasm and nucleus, mainly expressed in meristem regions, and promoted Cd, Fe, Mn, and Ca accumulation. SpGSH1 and SpPCS1 co-overexpression increased the Cd, Mn, and Ca contents. Based on the growth data of S. polyrhiza, it was recommended that biomass as the preferable indicator for assessing plant tolerance to Cd stress compared to frond number in duckweeds. Collectively, this study for the first time systematically elaborated the function of SpGSH1 and SpPCS1 for Cd detoxification in S. polyrhiza.

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Taste and odor (T&O) are among the most frequently encountered aesthetic issues in drinking water. While fungi have been reported to produce offensive odors, their contribution to T&O in drinking water remains understudied and often overlooked. In this study, the profiles of fungal community and odorants produced by 10 native fungal isolates were investigated in 36 samples collected from two drinking water treatment plants and a premise plumbing system. A total of 17 odorants were identified with Penicillium, Aspergillus, Paecilomyces, and Alternaria genera exhibiting the highest odorant yields. Significant concentrations of musty/earthy compounds were produced by these fungal isolates, such as 2-methylisoborneol (2-MIB) (26-256 ng/L), geosmin (10-13 ng/L), and 2-isobutyl-3-methoxy-pyrazine (IBMP) (3-13 ng/L). The high odor activity value of the odorants primarily occurred within 4 d, while toxicity continued to increase during the 8 d incubation. UV treatment in premise plumbing significantly (p < 0.05) reduced the gene read counts of Ascomycota phylum, Aspergillus spp., Fusarium spp., Rhizopus spp., and Trichoderma spp., by 2.3-4.0 times. These findings underscore the previously underestimated role of fungi in contributing to T&O issues in drinking water and corresponding risks to consumers and indicate UV as a promising strategy for fungal control in drinking water.

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The inflammatory microenvironment is a central driver of tumor metastasis, intimately associated with the promotion of epithelial-mesenchymal transition (EMT) and immune suppression. Here, transferrin-modified carprofen platinum(IV) nanoparticles Tf-NPs@CPF2-Pt(IV) with promising antiproliferative and antimetastatic properties were developed, which activated by inhibiting inflammation, suppressing EMT, and activating immune responses besides causing DNA injury. The nanoparticles released the active ingredient CPF2-Pt(IV) in a sustained manner and offered enhanced pharmacokinetic properties compared to free CPF2-Pt(IV) in vivo. Additionally, they possessed satisfactory tumor targeting effects via the transferrin motif. Serious DNA damage was induced with the upregulation of γ-H2AX and P53, and the mitochondria-mediated apoptotic pathway Bcl-2/Bax/caspase3 was initiated. Inflammation was alleviated by inhibiting COX-2 and MMP9 and decreasing inflammatory cytokines TNF-α and IL-6. Subsequently, the EMT was reversed by inhibiting the Wnt/ß-catenin pathway. Furthermore, the antitumor immunity was provoked by blocking the immune checkpoint PD-L1 and increasing CD3+ and CD8+ T lymphocytes in tumors.

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Radiomics offers a noninvasive avenue for predicting clinicopathological factors. However, thorough investigations into a robust breast cancer outcome-predicting model and its biological significance remain limited. This study develops a robust radiomic model for prognosis prediction, and further excavates its biological foundation and transferring prediction performance. We retrospectively collected preoperative dynamic contrast-enhanced MRI data from three distinct breast cancer patient cohorts. In FUSCC cohort (n = 466), Lasso was used to select features correlated with patient prognosis and multivariate Cox regression was utilized to integrate these features and build the radiomic risk model, while multiomic analysis was conducted to investigate the model's biological implications. DUKE cohort (n = 619) and I-SPY1 cohort (n = 128) were used to test the performance of the radiomic signature in outcome prediction. A thirteen-feature radiomic signature was identified in the FUSCC cohort training set and validated in the FUSCC cohort testing set, DUKE cohort and I-SPY1 cohort for predicting relapse-free survival (RFS) and overall survival (OS) (RFS: p = 0.013, p = 0.024 and p = 0.035; OS: p = 0.036, p = 0.005 and p = 0.027 in the three cohorts). Multiomic analysis uncovered metabolic dysregulation underlying the radiomic signature (ATP metabolic process: NES = 1.84, p-adjust = 0.02; cholesterol biosynthesis: NES = 1.79, p-adjust = 0.01). Regarding the therapeutic implications, the radiomic signature exhibited value when combining clinical factors for predicting the pathological complete response to neoadjuvant chemotherapy (DUKE cohort, AUC = 0.72; I-SPY1 cohort, AUC = 0.73). In conclusion, our study identified a breast cancer outcome-predicting radiomic signature in a multicenter radio-multiomic study, along with its correlations with multiomic features in prognostic risk assessment, laying the groundwork for future prospective clinical trials in personalized risk stratification and precision therapy.

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Neurodegenerative disorders are chronic conditions that progressively damage and destroy parts of the nervous system, and are currently considered permanent and incurable. Alternative strategies capable of effectively healing neuronal damage have been actively pursued. Here, we report the neuroprotective effects of baicalin (BA) combined with plasma-activated medium (PAM) against glutamate-induced excitotoxicity in SH-SY5Y cells. Through in vitro assays, the cell viability, inflammation, apoptosis, and oxidative stress were evaluated. The co-application of BA and PAM significantly enhanced cell viability, reduced pro-inflammatory markers (TNF-α and NF-κB), decreased apoptotic proteins (Bax and Caspase-3) and boosted antioxidative defenses (increased SOD activity and lowered ROS levels). This study confirms the potential of combining BA with PAM as an effective therapeutic strategy for mitigating the effects of excitotoxicity. PAM is a promising adjunct and potential drug delivery method in neuroprotective therapy, providing a new avenue for developing treatments for diseases characterized by neuronal damage.

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Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

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INTRODUCTION: Penile squamous cell carcinoma (PSCC) is a rare malignancy in men with poor survival in metastatic disease. Lynch syndrome (LS) is a cancer predisposition, autosomal-dominant, inherited disorder arises from loss of function variants in mismatch repair genes. CASE PRESENTATION: Here, we reported a PSCC patient who was suspected with LS caused by a heterozygous PMS2 D526Afs*69 variant. A 57-year-old male with PSCC underwent pelvic lymph node dissection and bilateral groin lymph node dissection due to metastatic disease. He has a family history of colon cancer and brain cancer. Comprehensive genomic sequencing of his tumor specimen identified 19 somatic mutations with a high tumor mutation burden (14.03 mutations per Mb) and a high frequency of microsatellite instability (MSI-H). Additionally, a germline PMS2 D526Afs*69 mutation was identified in the peripheral blood sample. Immunohistochemistry analysis showed complete loss of PMS2 and MLH1 expression in his tumor cells. CONCLUSION: These observations provided evidence suggesting that PSCC could be part of the LS spectrum.

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Pyrone-2,4-dicarboxylic acid (PDC) is a valuable polymer precursor that can be derived from the microbial degradation of lignin. The key enzyme in the microbial production of PDC is CHMS dehydrogenase, which acts on the substrate 4-carboxy-2-hydroxymuconate-6-semialdehyde (CHMS). We present the crystal structure of CHMS dehydrogenase (PmdC from Comamonas testosteroni) bound to the cofactor NADP, shedding light on its three-dimensional architecture, and revealing residues responsible for binding NADP. Using a combination of structural homology, molecular docking, and quantum chemistry calculations we have predicted the binding site of CHMS. Key histidine residues in a conserved sequence are identified as crucial for binding the hydroxyl group of CHMS and facilitating dehydrogenation with NADP. Mutating these histidine residues results in a loss of enzyme activity, leading to a proposed model for the enzyme's mechanism. These findings are expected to help guide efforts in protein and metabolic engineering to enhance PDC yields in biological routes to polymer feedstock synthesis.

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BACKGROUND: Rotational atherectomy (RA) remains an integral tool for the treatment of severe coronary calcified lesions despite emergence of newer techniques. We aimed to evaluate the contemporary clinical practices and outcomes of RA in China. METHODS: The Rota China Registry (NCT03806621) was an investigator-initiated, prospective, multicenter registry based on China Rota Elite Group. Consecutive patients treated with RA were recruited. A pre-designed, standardized protocol was recommended for the RA procedure. The primary safety endpoint was major adverse cardiovascular events (MACE: composite of cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 30 days. The primary efficacy endpoint was procedural success. RESULTS: Between July 2018 and December 2020, 980 patients were enrolled at 19 sites in China. Mean patient age was 68.4 years, and 61.4% were men. Radial access was used in 79.1% patients, and 32.7% procedures were guided by intravascular imaging. A total of 22.6% procedures used more than 1 burr, and the maximal burr size was ≥1.75 mm in 24.4% cases, with burr upsizing in 19.3% cases, achieving a final burr-to-artery ratio of 0.52. Procedural success was achieved in 91.1% of patients, and the rate of 30-day and 1-year MACE was 4.9% and 8.2%, respectively. Multivariable analysis identified the total lesion length (HR 1.014, 95% CI: 1.002-1.027; p = 0.021) as predictor of 30-day MACE, and renal insufficiency (HR 1.916, 95% CI: 1.073-3.420; p = 0.028) as predictor of 1-year MACE. CONCLUSIONS: In this contemporary prospective registry in China, the use of RA was effective in achieving high procedural success rate with good short- and long-term outcomes in patients with severely calcified lesions.

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Quasi-two-dimensional (Q-2D) perovskites show great potential in the field of photonic and optoelectronic device applications. However, defects and local lattice dislocation still limit performance and stability improvement by nonradiative recombination, unpreferred phase distribution, and unbonded amines. Here, a low-temperature synergistic strategy for both reconstructing and solidifying the perovskite top and buried interface is developed. By post-treating the 1,4-phenylenedimethanammonium (PDMA) based (PDMA)MA4Pb5I16 films with cesium acetate (CsAc) before thermal annealing, a condensation reaction between R-COO- and -NH2 and ion exchange between Cs+ and MA+ occur. It converts the unbonded amines to amides and passivates uncoordinated Pb2+. Meanwhile, it adjusts film composition and improves the phase distribution without changing the out-of-plane grain orientation. Consequently, performance of 18.1% and much-enhanced stability (e.g., stability for photo-oxygen increased over 10 times, light-thermal for T90 over 4 times, and reverse bias over 3 times) of (PDMA)MA4Pb5I16 perovskite solar cells are demonstrated.

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BACKGROUND: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using two mouse models of concurrent chronic pain and depression. METHODS: C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior. RESULTS: This induction of chronic pain and depression in the two animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB and p65. cAMP agonist forskolin, reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice. CONCLUSIONS: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression.

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The single-nucleotide polymorphisms of genes related to DNA damage repair and inflammasomes and mutated gene expression in coal workers' pneumoconiosis (CWP) were analysed to identify the risk factors of CWP and potential biomarkers for early warning and diagnosis. Further, mutated gene pathways were analysed based on proteome and metabolome. Han Chinese male subjects were randomly selected and divided into 4 or 5 groups according to the process of CWP. MassARRAY was used to sequence single-nucleotide polymorphism genotypes. Mutated gene expression in plasma was tested using enzyme-linked immunosorbent assay (ELISA). Odds ratios (ORs) and receiver operating characteristic curves (ROC) were calculated. The serum different proteins and metabolites were identified by Ultra Performance Liquid Chromatography Quadrupole time of flight/Mass Spectrum (UPLC-Q-TOF/MS) and analysed using bioinformation software. As CWP progressed, the CC and CA genotypes of ERCC1 rs3212986 decreased and increased significantly, respectively. AA (OR = 3.016) and CA (OR = 2.130) genotypes were identified as risk factors for stage II. ERCC1 significantly decreased in processing of CWP. The cutoff value of ERCC1 was 5.265 pg/ml, with a sensitivity of 90.0% and specificity of 86.7%. ERCC1 had an indirect interaction with activator protein-1 and insulin and its pathways were mainly made with molecules related to lipid metabolism and actin dynamics. ERCC1 is a candidate biomarker for detection and precise intervention in CWP. If it reaches the threshold, workers will change other jobs in time and will not develop and diagnose as pneumoconiosis and will help the employers spend less money. Meanwhile, the signal molecules of ERCC1 pathway could be as a candidate target for drug discovery.

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Background: Tumor budding (TB) has been shown to be a poor prognostic indicator after colorectal cancer (CRC) surgery. The aim of the present study is to evaluate the predictive role of morphological features (e.g., the number, structure, and location of tumor buds, and their reaction with the extracellular mesenchyme) in postoperative adjuvant chemotherapy in surgically resectable stage II CRC. Methods: Between 2016 and 2019, 336 patients with stage II CRC who underwent radical surgery were enrolled in this study. TB status was determined according to the criteria adopted at the 2016 International Tumor Budding Consensus Conference (ITBCC). We retrospectively recorded all the clinical and pathological data and assessed the effect of different types of TB status on patients' recurrence-free survival (RFS) and overall survival (OS). Results: Of the 336 patients, 173, 88, and 75 were budding grade 1 (BD1), BD2, and BD3, respectively. The 5-year RFS rates were 84.6%, 81.2%, and 68.0% (P=0.01), and the 5-year OS rates were 91.0%, 83.3%, and 76.2% (P=0.007) in BD1, BD2, and BD3, respectively. TB grade was strongly associated with vascular invasion status and mucinous adenocarcinoma, and BD3 was detected in 51.7% of patients with positive vascular invasion. The multivariate analysis showed that only age, perineural invasion, and TB grade [BD2 vs. BD1, hazard ratio (HR) =1.468, 95% confidence interval (CI): 0.703-3.063, P=0.30; BD3 vs. BD1, HR =2.310, 95% CI: 1.154-4.625, P=0.01] had an independent effect on RFS. In addition, the Kaplan-Meier curve analysis showed that BD3 patients had the worst RFS (P=0.01). The OS of the adjuvant chemotherapy group was significantly improved compared to that of the surgery-only group in the BD1/2 patients (HR =0.278, 95% CI: 0.114-0.676, P=0.005) but not in the BD3 patients with significant interaction (Pinteraction=0.03). Conclusions: Our results indicate that TB could play a subsidiary role in selecting stage II CRC patients who could achieve a favorable prognosis with chemotherapy.

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Background: Prior studies indicate that lactylation regulates various biological mechanisms within cancer. However, lactylation-related genes (LRGs) have been found to have limited value in predicting the prognosis of hepatocellular carcinoma (HCC). The aim of this study was to review HCC LRGs using data from The Cancer Genome Atlas (TCGA). Methods: The RNA sequencing data and related clinical information of patients with HCC patients were collected from the TCGA database. A total of 20 LRGs were selected and bioinformatics analysis was performed. A consistency cluster analysis was conducted to classify the HCC tumors. Using a lactylation-related model of HCC, prognosis, immune cell infiltration, and immunotherapy was evaluated. Results: A total of 4,378 genes were associated with prognosis. Twenty LRGs (i.e., ACIN1, RAN, PPP1CB, ALDOB, SUMO2, THOC2, HDAC1, SF3A1, SF3B1, HNRNPM, PPP1CC, SRRM1, PRPF6, HDAC2, H2AFV, ALYREF, H2AFZ, H2AFX, HNRNPK, and MAGOH) were identified. The 20 LRGs were used to divide TCGA-HCC patients into low-risk (G1) and high-risk (G2) categories. The upregulated genes in the G1 group primarily participate in the p53 signaling pathway, focal adhesion, extracellular matrix (ECM)-receptor interaction, and cell cycle, while the downregulated genes primarily participate in the glycolysis/gluconeogenesis, carbon metabolism, and biosynthesis of amino acids. The box plots showed a significant difference in the immune cell populations, with a higher abundance of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and myeloid dendritic cells in the G1 than the G2 HCC samples. Further, the box plots showed higher expression levels of seven of the eight immune checkpoint inhibitor (ICI)-related genes in the G1 HCC samples than the G2 samples. There was a significant disparity in the cancer stem cell (CSC) scores between the G1 and G2 TCGA-HCC patients. Additionally, the G1 TCGA-HCC patients had higher tumor immune dysfunction and exclusion (TIDE) scores than the G2 TCGA-HCC patients. The prognosis of the HCC patients was also predicted using a six-LRG model, comprising HDAC2, SRRM1, SF3B1, HDAC1, THOC2, and PPP1CB. Conclusions: Strong correlation between LRGs and tumor classification as well as immunity in patients with HCC was identified. LRG signatures serve as reliable prognostic markers for HCC.